Naturehttp://www.nature.com/includes/rj_globnavimages/nature_logo.gifhttp://www.nature.com/nature/
Against discriminationhttp://dx.doi.org/10.1038/548259b
Science cannot and should not be used to justify prejudice.Against discrimination

Funding trouble at flagship research centre reflects a broader malaise in the country’s scientific priorities that must be addressed.

]]>Budget cuts fuel frustration among Japan’s academicsdoi:10.1038/nature.2017.22444Nature 548, 7667 (2017)2017-08-14Nature2017-08-1410.1038/nature.2017.22444http://dx.doi.org/10.1038/nature.2017.224445487667Editorial259259A little democracy could go a long wayhttp://www.nature.com/doifinder/10.1038/548261a
The Middle East is freezing out Qatar. A science academy could help — and would set an important precedent for the region, says Ehsan Masood.A little democracy could go a long way

]]>Massive El Niño sent greenhouse-gas emissions soaringGabriel Popkindoi:10.1038/nature.2017.22440Nature 548, 7667 (2017)2017-08-10Nature2017-08-1010.1038/nature.2017.22440http://www.nature.com/doifinder/10.1038/nature.2017.224405487667News269269Thousands across India march in support of sciencehttp://www.nature.com/doifinder/10.1038/nature.2017.22439
Protesters demand respect for research — but some scientists were told to stay away.Thousands across India march in support of science

Protesters demand respect for research — but some scientists were told to stay away.

]]>Thousands across India march in support of scienceT. V. Padmadoi:10.1038/nature.2017.22439Nature 548, 7667 (2017)2017-08-09Nature2017-08-0910.1038/nature.2017.22439http://www.nature.com/doifinder/10.1038/nature.2017.224395487667News270270US biomedical-research facilities unprepared for attacks and natural disastershttp://www.nature.com/doifinder/10.1038/nature.2017.22446
Science panel says institutions need to do more to prevent and mitigate damage to research equipment and animals.US biomedical-research facilities unprepared for attacks and natural disasters

Roger Bilham savours two rich accounts of seismicity across the continent.

]]>Seismology: Quake news from AmericaRoger Bilhamdoi:10.1038/548278aNature 548, 7667 (2017)2017-08-16Nature2017-08-1610.1038/548278ahttp://dx.doi.org/10.1038/548278a5487667Books and Arts278280Books in briefhttp://dx.doi.org/10.1038/548279a
Barbara Kiser reviews five of the week's best science picks.Books in brief

]]>Books in briefBarbara Kiserdoi:10.1038/548279aNature 548, 7667 (2017)2017-08-16Nature2017-08-1610.1038/548279ahttp://dx.doi.org/10.1038/548279a5487667Books and Arts279279Data sharing: guard the privacy of donorshttp://dx.doi.org/10.1038/548281a
I endorse Emma Kowal and colleagues' call for more-responsible sharing of people's research data (Nature546, 474;10.1038/546474a2017). The reuse of data without participants' consent is a serious ethical problem and could discourage participation in future projects (see, for example, Data sharing: guard the privacy of donors

I endorse Emma Kowal and colleagues' call for more-responsible sharing of people's research data (Nature546, 474;10.1038/546474a2017). The reuse of data without participants' consent is a serious ethical problem and could discourage participation in future projects (see, for example,

The movement of people and infrastructure out of vulnerable areas, a process called managed retreat, is gaining recognition as a potential adaptation strategy to climate change and natural hazards (see also M.Hinoet al. Nature Clim. Change7, 364–370;

]]>Climate adaptation: Past US floods give lessons in retreatA. R. Sidersdoi:10.1038/548281cNature 548, 7667 (2017)2017-08-16Nature2017-08-1610.1038/548281chttp://dx.doi.org/10.1038/548281c5487667Correspondence281281Carbon emissions: More nuclear power can speed CO2 cutshttp://dx.doi.org/10.1038/548281d
Christiana Figueres and colleagues note that turning around global carbon dioxide emissions by 2020 may not be feasible through renewable energy alone (Nature546, 593–595;10.1038/546593a2017). Low-carbon nuclear power will be needed as well.Historically, energy transitions take Carbon emissions: More nuclear power can speed CO2 cuts

Christiana Figueres and colleagues note that turning around global carbon dioxide emissions by 2020 may not be feasible through renewable energy alone (Nature546, 593–595;10.1038/546593a2017). Low-carbon nuclear power will be needed as well.Historically, energy transitions take

]]>Carbon emissions: More nuclear power can speed CO2 cutsRichard Rhodesdoi:10.1038/548281dNature 548, 7667 (2017)2017-08-16Nature2017-08-1610.1038/548281dhttp://dx.doi.org/10.1038/548281d5487667Correspondence281281History: Ingenious solutions sparked by a crisishttp://dx.doi.org/10.1038/548281e
Researchers have taken to recycling laboratory helium in the face of dwindling supplies resulting from the blockade of Qatar (Nature547, 16;10.1038/547016a2017). Such extreme situations have also prompted other scientists to devise imaginative alternatives in the past.In the History: Ingenious solutions sparked by a crisis

Researchers have taken to recycling laboratory helium in the face of dwindling supplies resulting from the blockade of Qatar (Nature547, 16;10.1038/547016a2017). Such extreme situations have also prompted other scientists to devise imaginative alternatives in the past.In the

]]>History: Ingenious solutions sparked by a crisisBiswa Prasun Chatterjidoi:10.1038/548281eNature 548, 7667 (2017)2017-08-16Nature2017-08-1610.1038/548281ehttp://dx.doi.org/10.1038/548281e5487667Correspondence281281Student immigration: The gamble of going abroadhttp://dx.doi.org/10.1038/nj7667-361a
Political concerns and visa access are swaying students deciding where to pursue a degree.Student immigration: The gamble of going abroad

]]>First date with the HiveGretchen Tessmerdoi:10.1038/548366aNature 548, 7667 (2017)2017-08-16Nature2017-08-1610.1038/548366ahttp://dx.doi.org/10.1038/548366a5487667Futures366366Climate science: Origins of Atlantic decadal swingshttp://dx.doi.org/10.1038/nature23538
Temperature variability in the North Atlantic Ocean is the result of many competing physical processes, but the relative roles of these processes is a source of contention. Here, scientists present two perspectives on the debate.Climate science: Origins of Atlantic decadal swings

Temperature variability in the North Atlantic Ocean is the result of many competing physical processes, but the relative roles of these processes is a source of contention. Here, scientists present two perspectives on the debate.

]]>Climate science: Origins of Atlantic decadal swingsGabriel A. VecchiThomas L. DelworthBen Boothdoi:10.1038/nature23538Nature 548, 7667 (2017)2017-08-09Nature2017-08-0910.1038/nature23538http://dx.doi.org/10.1038/nature235385487667News & Views284285Neurobiology: A bitter–sweet symphonyhttp://dx.doi.org/10.1038/nature23537
Information about taste sensations, such as bitter or sweet, is relayed from the mouse tongue to the brain through taste-specific pathways. It emerges that semaphorin proteins guide the wiring of these pathways. See Letter p.330Neurobiology: A bitter–sweet symphony

Information about taste sensations, such as bitter or sweet, is relayed from the mouse tongue to the brain through taste-specific pathways. It emerges that semaphorin proteins guide the wiring of these pathways. See Letter p.330

]]>Neurobiology: A bitter–sweet symphonyJiefu LiLiqun Luodoi:10.1038/nature23537Nature 548, 7667 (2017)2017-08-09Nature2017-08-0910.1038/nature23537http://dx.doi.org/10.1038/nature235375487667News & Views285287Cancer genomics: Human metastases under scrutinyhttp://dx.doi.org/10.1038/nature23535
Sequences of the DNA and RNA of 500 human cancers that have spread from their primary site in the body take us a step closer to the convergence of basic science and patient benefit. See Article p.297Cancer genomics: Human metastases under scrutiny

Sequences of the DNA and RNA of 500 human cancers that have spread from their primary site in the body take us a step closer to the convergence of basic science and patient benefit. See Article p.297

]]>Cancer genomics: Human metastases under scrutinyG. Steven Bovadoi:10.1038/nature23535Nature 548, 7667 (2017)2017-08-02Nature2017-08-0210.1038/nature23535http://dx.doi.org/10.1038/nature235355487667News & Views287288Astronomy: A turbulent stellar atmosphere in full viewhttp://dx.doi.org/10.1038/548288a
The dynamic motion of gas in the outer atmosphere of a red supergiant star has been mapped, providing clues to the mysterious mechanism that causes massive stars to lose mass through stellar winds. See Letter p.310Astronomy: A turbulent stellar atmosphere in full view

The dynamic motion of gas in the outer atmosphere of a red supergiant star has been mapped, providing clues to the mysterious mechanism that causes massive stars to lose mass through stellar winds. See Letter p.310

Live imaging shows that healthy skin cells surround and expel neighbours that have cancer-promoting mutations, revealing that tissues can recognize and eliminate mutant cells to prevent tumour initiation. See Letter p.334

]]>Cell biology: Healthy skin rejects cancerJoseph BurclaffJason C. Millsdoi:10.1038/nature23534Nature 548, 7667 (2017)2017-08-02Nature2017-08-0210.1038/nature23534http://dx.doi.org/10.1038/nature235345487667News & Views289290New gliding mammaliaforms from the Jurassichttp://dx.doi.org/10.1038/nature23476
Stem mammaliaforms are Mesozoic forerunners to mammals, and they offer critical evidence for the anatomical evolution and ecological diversification during the earliest mammalian history. Two new eleutherodonts from the Late Jurassic period have skin membranes and skeletal features that are adapted for gliding. Characteristics of New gliding mammaliaforms from the Jurassic

Stem mammaliaforms are Mesozoic forerunners to mammals, and they offer critical evidence for the anatomical evolution and ecological diversification during the earliest mammalian history. Two new eleutherodonts from the Late Jurassic period have skin membranes and skeletal features that are adapted for gliding. Characteristics of

Metastasis is the primary cause of cancer-related deaths. Although The Cancer Genome Atlas has sequenced primary tumour types obtained from surgical resections, much less comprehensive molecular analysis is available from clinically acquired metastatic cancers. Here we perform whole-exome and -transcriptome sequencing of 500 adult patients

]]>Integrative clinical genomics of metastatic cancerDan R. RobinsonYi-Mi WuRobert J. LonigroPankaj VatsErin CobainJessica EverettXuhong CaoErica RabbanChandan Kumar-SinhaVictoria RaymondScott SchuetzeAjjai AlvaJaved SiddiquiRashmi ChughFrancis WordenMark M. ZalupskiJeffrey InnisRajen J. ModyScott A. TomlinsDavid LucasLaurence H. BakerNithya RamnathAnn F. SchottDaniel F. HayesJoseph VijaiKenneth OffitElena M. StoffelJ. Scott RobertsDavid C. SmithLakshmi P. KunjuMoshe TalpazMarcin CieślikArul M. Chinnaiyandoi:10.1038/nature23306Nature 548, 7667 (2017)2017-08-02Nature2017-08-0210.1038/nature23306http://dx.doi.org/10.1038/nature233065487667Article297303Ram-pressure feeding of supermassive black holeshttp://dx.doi.org/10.1038/nature23462
When a supermassive black hole at the centre of a galaxy accretes matter, it gives rise to a highly energetic phenomenon: an active galactic nucleus. Numerous physical processes have been proposed to account for the funnelling of gas towards the galactic centre to feed the black hole. There are also several physical processes that can remove gas from a galaxy, one of which is ram-pressure stripping by the hot gas that fills the space between galaxies in galaxy clusters. Here we report that six out of a sample of seven ‘jellyfish’ galaxies—galaxies with long ‘tentacles’ of material that extend for dozens of kiloparsecs beyond the galactic disks—host an active nucleus, and two of them also have galactic-scale ionization cones. The high incidence of nuclear activity among heavily stripped jellyfish galaxies may be due to ram pressure causing gas to flow towards the centre and triggering the activity, or to an enhancement of the stripping caused by energy injection from the active nucleus, or both. Our analysis of the galactic position and velocity relative to the cluster strongly supports the first hypothesis, and puts forward ram pressure as another possible mechanism for feeding the central supermassive black hole with gas.Ram-pressure feeding of supermassive black holes

When a supermassive black hole at the centre of a galaxy accretes matter, it gives rise to a highly energetic phenomenon: an active galactic nucleus. Numerous physical processes have been proposed to account for the funnelling of gas towards the galactic centre to feed the black hole. There are also several physical processes that can remove gas from a galaxy, one of which is ram-pressure stripping by the hot gas that fills the space between galaxies in galaxy clusters. Here we report that six out of a sample of seven ‘jellyfish’ galaxies—galaxies with long ‘tentacles’ of material that extend for dozens of kiloparsecs beyond the galactic disks—host an active nucleus, and two of them also have galactic-scale ionization cones. The high incidence of nuclear activity among heavily stripped jellyfish galaxies may be due to ram pressure causing gas to flow towards the centre and triggering the activity, or to an enhancement of the stripping caused by energy injection from the active nucleus, or both. Our analysis of the galactic position and velocity relative to the cluster strongly supports the first hypothesis, and puts forward ram pressure as another possible mechanism for feeding the central supermassive black hole with gas.

]]>Ram-pressure feeding of supermassive black holesBianca M. PoggiantiYara L. JafféAlessia MorettiMarco GullieuszikMario RadovichStephanie TonnesenJacopo FritzDaniela BettoniBenedetta VulcaniGiovanni FasanoCallum BellhouseGeorge HauAlessandro Omizzolodoi:10.1038/nature23462Nature 548, 7667 (2017)2017-08-16Nature2017-08-1610.1038/nature23462http://dx.doi.org/10.1038/nature234625487667Letter304309Vigorous atmospheric motion in the red supergiant star Antareshttp://dx.doi.org/10.1038/nature23445
Red supergiant stars represent a late stage of the evolution of stars more massive than about nine solar masses, in which they develop complex, multi-component atmospheres. Bright spots have been detected in the atmosphere of red supergiants using interferometric imaging. Above the photosphere of a red supergiant, the molecular outer atmosphere extends up to about two stellar radii. Furthermore, the hot chromosphere (5,000 to 8,000 kelvin) and cool gas (less than 3,500 kelvin) of a red supergiant coexist at about three stellar radii. The dynamics of such complex atmospheres has been probed by ultraviolet and optical spectroscopy. The most direct approach, however, is to measure the velocity of gas at each position over the image of stars as in observations of the Sun. Here we report the mapping of the velocity field over the surface and atmosphere of the nearby red supergiant Antares. The two-dimensional velocity field map obtained from our near-infrared spectro-interferometric imaging reveals vigorous upwelling and downdrafting motions of several huge gas clumps at velocities ranging from about −20 to +20 kilometres per second in the atmosphere, which extends out to about 1.7 stellar radii. Convection alone cannot explain the observed turbulent motions and atmospheric extension, suggesting that an unidentified process is operating in the extended atmosphere.Vigorous atmospheric motion in the red supergiant star Antares

Red supergiant stars represent a late stage of the evolution of stars more massive than about nine solar masses, in which they develop complex, multi-component atmospheres. Bright spots have been detected in the atmosphere of red supergiants using interferometric imaging. Above the photosphere of a red supergiant, the molecular outer atmosphere extends up to about two stellar radii. Furthermore, the hot chromosphere (5,000 to 8,000 kelvin) and cool gas (less than 3,500 kelvin) of a red supergiant coexist at about three stellar radii. The dynamics of such complex atmospheres has been probed by ultraviolet and optical spectroscopy. The most direct approach, however, is to measure the velocity of gas at each position over the image of stars as in observations of the Sun. Here we report the mapping of the velocity field over the surface and atmosphere of the nearby red supergiant Antares. The two-dimensional velocity field map obtained from our near-infrared spectro-interferometric imaging reveals vigorous upwelling and downdrafting motions of several huge gas clumps at velocities ranging from about −20 to +20 kilometres per second in the atmosphere, which extends out to about 1.7 stellar radii. Convection alone cannot explain the observed turbulent motions and atmospheric extension, suggesting that an unidentified process is operating in the extended atmosphere.

]]>Vigorous atmospheric motion in the red supergiant star AntaresK. OhnakaG. WeigeltK.-H. Hofmanndoi:10.1038/nature23445Nature 548, 7667 (2017)2017-08-16Nature2017-08-1610.1038/nature23445http://dx.doi.org/10.1038/nature234455487667Letter310312Electronic in-plane symmetry breaking at field-tuned quantum criticality in CeRhIn5http://dx.doi.org/10.1038/nature23315
Electronic nematic materials are characterized by a lowered symmetry of the electronic system compared to the underlying lattice, in analogy to the directional alignment without translational order in nematic liquid crystals. Such nematic phases appear in the copper- and iron-based high-temperature superconductors, and their role in establishing superconductivity remains an open question. Nematicity may take an active part, cooperating or competing with superconductivity, or may appear accidentally in such systems. Here we present experimental evidence for a phase of fluctuating nematic character in a heavy-fermion superconductor, CeRhIn5 (ref. 5). We observe a magnetic-field-induced state in the vicinity of a field-tuned antiferromagnetic quantum critical point at Hc ≈ 50 tesla. This phase appears above an out-of-plane critical field H* ≈ 28 tesla and is characterized by a substantial in-plane resistivity anisotropy in the presence of a small in-plane field component. The in-plane symmetry breaking has little apparent connection to the underlying lattice, as evidenced by the small magnitude of the magnetostriction anomaly at H*. Furthermore, no anomalies appear in the magnetic torque, suggesting the absence of metamagnetism in this field range. The appearance of nematic behaviour in a prototypical heavy-fermion superconductor highlights the interrelation of nematicity and unconventional superconductivity, suggesting nematicity to be common among correlated materials.Electronic in-plane symmetry breaking at field-tuned quantum criticality in CeRhIn5

Electronic nematic materials are characterized by a lowered symmetry of the electronic system compared to the underlying lattice, in analogy to the directional alignment without translational order in nematic liquid crystals. Such nematic phases appear in the copper- and iron-based high-temperature superconductors, and their role in establishing superconductivity remains an open question. Nematicity may take an active part, cooperating or competing with superconductivity, or may appear accidentally in such systems. Here we present experimental evidence for a phase of fluctuating nematic character in a heavy-fermion superconductor, CeRhIn5 (ref. 5). We observe a magnetic-field-induced state in the vicinity of a field-tuned antiferromagnetic quantum critical point at Hc ≈ 50 tesla. This phase appears above an out-of-plane critical field H* ≈ 28 tesla and is characterized by a substantial in-plane resistivity anisotropy in the presence of a small in-plane field component. The in-plane symmetry breaking has little apparent connection to the underlying lattice, as evidenced by the small magnitude of the magnetostriction anomaly at H*. Furthermore, no anomalies appear in the magnetic torque, suggesting the absence of metamagnetism in this field range. The appearance of nematic behaviour in a prototypical heavy-fermion superconductor highlights the interrelation of nematicity and unconventional superconductivity, suggesting nematicity to be common among correlated materials.

]]>Electronic in-plane symmetry breaking at field-tuned quantum criticality in CeRhIn5F. RonningT. HelmK. R. ShirerM. D. BachmannL. BalicasM. K. ChanB. J. RamshawR. D. McDonaldF. F. BalakirevM. JaimeE. D. BauerP. J. W. Molldoi:10.1038/nature23315Nature 548, 7667 (2017)2017-08-07Nature2017-08-0710.1038/nature23315http://dx.doi.org/10.1038/nature233155487667Letter313317Chaotic dynamics in nanoscale NbO2 Mott memristors for analogue computinghttp://dx.doi.org/10.1038/nature23307
At present, machine learning systems use simplified neuron models that lack the rich nonlinear phenomena observed in biological systems, which display spatio-temporal cooperative dynamics. There is evidence that neurons operate in a regime called the edge of chaos that may be central to complexity, learning efficiency, adaptability and analogue (non-Boolean) computation in brains. Neural networks have exhibited enhanced computational complexity when operated at the edge of chaos, and networks of chaotic elements have been proposed for solving combinatorial or global optimization problems. Thus, a source of controllable chaotic behaviour that can be incorporated into a neural-inspired circuit may be an essential component of future computational systems. Such chaotic elements have been simulated using elaborate transistor circuits that simulate known equations of chaos, but an experimental realization of chaotic dynamics from a single scalable electronic device has been lacking. Here we describe niobium dioxide (NbO2) Mott memristors each less than 100 nanometres across that exhibit both a nonlinear-transport-driven current-controlled negative differential resistance and a Mott-transition-driven temperature-controlled negative differential resistance. Mott materials have a temperature-dependent metal–insulator transition that acts as an electronic switch, which introduces a history-dependent resistance into the device. We incorporate these memristors into a relaxation oscillator and observe a tunable range of periodic and chaotic self-oscillations. We show that the nonlinear current transport coupled with thermal fluctuations at the nanoscale generates chaotic oscillations. Such memristors could be useful in certain types of neural-inspired computation by introducing a pseudo-random signal that prevents global synchronization and could also assist in finding a global minimum during a constrained search. We specifically demonstrate that incorporating such memristors into the hardware of a Hopfield computing network can greatly improve the efficiency and accuracy of converging to a solution for computationally difficult problems.Chaotic dynamics in nanoscale NbO2 Mott memristors for analogue computing

At present, machine learning systems use simplified neuron models that lack the rich nonlinear phenomena observed in biological systems, which display spatio-temporal cooperative dynamics. There is evidence that neurons operate in a regime called the edge of chaos that may be central to complexity, learning efficiency, adaptability and analogue (non-Boolean) computation in brains. Neural networks have exhibited enhanced computational complexity when operated at the edge of chaos, and networks of chaotic elements have been proposed for solving combinatorial or global optimization problems. Thus, a source of controllable chaotic behaviour that can be incorporated into a neural-inspired circuit may be an essential component of future computational systems. Such chaotic elements have been simulated using elaborate transistor circuits that simulate known equations of chaos, but an experimental realization of chaotic dynamics from a single scalable electronic device has been lacking. Here we describe niobium dioxide (NbO2) Mott memristors each less than 100 nanometres across that exhibit both a nonlinear-transport-driven current-controlled negative differential resistance and a Mott-transition-driven temperature-controlled negative differential resistance. Mott materials have a temperature-dependent metal–insulator transition that acts as an electronic switch, which introduces a history-dependent resistance into the device. We incorporate these memristors into a relaxation oscillator and observe a tunable range of periodic and chaotic self-oscillations. We show that the nonlinear current transport coupled with thermal fluctuations at the nanoscale generates chaotic oscillations. Such memristors could be useful in certain types of neural-inspired computation by introducing a pseudo-random signal that prevents global synchronization and could also assist in finding a global minimum during a constrained search. We specifically demonstrate that incorporating such memristors into the hardware of a Hopfield computing network can greatly improve the efficiency and accuracy of converging to a solution for computationally difficult problems.

]]>Chaotic dynamics in nanoscale NbO2 Mott memristors for analogue computingSuhas KumarJohn Paul StrachanR. Stanley Williamsdoi:10.1038/nature23307Nature 548, 7667 (2017)2017-08-09Nature2017-08-0910.1038/nature23307http://dx.doi.org/10.1038/nature233075487667Letter318321An early modern human presence in Sumatra 73,000–63,000 years agohttp://dx.doi.org/10.1038/nature23452
Genetic evidence for anatomically modern humans (AMH) out of Africa before 75 thousand years ago (ka) and in island southeast Asia (ISEA) before 60 ka (93–61 ka) predates accepted archaeological records of occupation in the region. Claims that AMH arrived in ISEA before 60 ka (ref. 4) have been supported only by equivocal or non-skeletal evidence. AMH evidence from this period is rare and lacks robust chronologies owing to a lack of direct dating applications, poor preservation and/or excavation strategies and questionable taxonomic identifications. Lida Ajer is a Sumatran Pleistocene cave with a rich rainforest fauna associated with fossil human teeth. The importance of the site is unclear owing to unsupported taxonomic identification of these fossils and uncertainties regarding the age of the deposit, therefore it is rarely considered in models of human dispersal. Here we reinvestigate Lida Ajer to identify the teeth confidently and establish a robust chronology using an integrated dating approach. Using enamel–dentine junction morphology, enamel thickness and comparative morphology, we show that the teeth are unequivocally AMH. Luminescence and uranium-series techniques applied to bone-bearing sediments and speleothems, and coupled uranium-series and electron spin resonance dating of mammalian teeth, place modern humans in Sumatra between 73 and 63 ka. This age is consistent with biostratigraphic estimations, palaeoclimate and sea-level reconstructions, and genetic evidence for a pre-60 ka arrival of AMH into ISEA. Lida Ajer represents, to our knowledge, the earliest evidence of rainforest occupation by AMH, and underscores the importance of reassessing the timing and environmental context of the dispersal of modern humans out of Africa.An early modern human presence in Sumatra 73,000–63,000 years ago

Genetic evidence for anatomically modern humans (AMH) out of Africa before 75 thousand years ago (ka) and in island southeast Asia (ISEA) before 60 ka (93–61 ka) predates accepted archaeological records of occupation in the region. Claims that AMH arrived in ISEA before 60 ka (ref. 4) have been supported only by equivocal or non-skeletal evidence. AMH evidence from this period is rare and lacks robust chronologies owing to a lack of direct dating applications, poor preservation and/or excavation strategies and questionable taxonomic identifications. Lida Ajer is a Sumatran Pleistocene cave with a rich rainforest fauna associated with fossil human teeth. The importance of the site is unclear owing to unsupported taxonomic identification of these fossils and uncertainties regarding the age of the deposit, therefore it is rarely considered in models of human dispersal. Here we reinvestigate Lida Ajer to identify the teeth confidently and establish a robust chronology using an integrated dating approach. Using enamel–dentine junction morphology, enamel thickness and comparative morphology, we show that the teeth are unequivocally AMH. Luminescence and uranium-series techniques applied to bone-bearing sediments and speleothems, and coupled uranium-series and electron spin resonance dating of mammalian teeth, place modern humans in Sumatra between 73 and 63 ka. This age is consistent with biostratigraphic estimations, palaeoclimate and sea-level reconstructions, and genetic evidence for a pre-60 ka arrival of AMH into ISEA. Lida Ajer represents, to our knowledge, the earliest evidence of rainforest occupation by AMH, and underscores the importance of reassessing the timing and environmental context of the dispersal of modern humans out of Africa.

]]>An early modern human presence in Sumatra 73,000–63,000 years agoK. E. WestawayJ. LouysR. Due AweM. J. MorwoodG. J. PriceJ.-x. ZhaoM. AubertR. Joannes-BoyauT. M. SmithM. M. SkinnerT. ComptonR. M. BaileyG. D. van den BerghJ. de VosA. W. G. PikeC. StringerE. W. SaptomoY. RizalJ. ZaimW. D. SantosoA. TrihascaryoL. KinsleyB. Sulistyantodoi:10.1038/nature23452Nature 548, 7667 (2017)2017-08-09Nature2017-08-0910.1038/nature23452http://dx.doi.org/10.1038/nature234525487667Letter322325New evidence for mammaliaform ear evolution and feeding adaptation in a Jurassic ecosystemhttp://dx.doi.org/10.1038/nature23483
Stem mammaliaforms are forerunners to modern mammals, and they achieved considerable ecomorphological diversity in their own right. Recent discoveries suggest that eleutherodontids, a subclade of Haramiyida, were more species-rich during the Jurassic period in Asia than previously recognized. Here we report a new Jurassic eleutherodontid mammaliaform with an unusual mosaic of highly specialized characteristics, and the results of phylogenetic analyses that support the hypothesis that haramiyidans are stem mammaliaforms. The new fossil shows fossilized skin membranes that are interpreted to be for gliding and a mandibular middle ear with a unique character combination previously unknown in mammaliaforms. Incisor replacement is prolonged until well after molars are fully erupted, a timing pattern unique to most other mammaliaforms. In situ molar occlusion and a functional analysis reveal a new mode of dental occlusion: dual mortar–pestle occlusion of opposing upper and lower molars, probably for dual crushing and grinding. This suggests that eleutherodontids are herbivorous, and probably specialized for granivory or feeding on soft plant tissues. The inferred dietary adaptation of eleutherodontid gliders represents a remarkable evolutionary convergence with herbivorous gliders in Theria. These Jurassic fossils represent volant, herbivorous stem mammaliaforms associated with pre-angiosperm plants that appear long before the later, iterative associations between angiosperm plants and volant herbivores in various therian clades.New evidence for mammaliaform ear evolution and feeding adaptation in a Jurassic ecosystem

Stem mammaliaforms are forerunners to modern mammals, and they achieved considerable ecomorphological diversity in their own right. Recent discoveries suggest that eleutherodontids, a subclade of Haramiyida, were more species-rich during the Jurassic period in Asia than previously recognized. Here we report a new Jurassic eleutherodontid mammaliaform with an unusual mosaic of highly specialized characteristics, and the results of phylogenetic analyses that support the hypothesis that haramiyidans are stem mammaliaforms. The new fossil shows fossilized skin membranes that are interpreted to be for gliding and a mandibular middle ear with a unique character combination previously unknown in mammaliaforms. Incisor replacement is prolonged until well after molars are fully erupted, a timing pattern unique to most other mammaliaforms. In situ molar occlusion and a functional analysis reveal a new mode of dental occlusion: dual mortar–pestle occlusion of opposing upper and lower molars, probably for dual crushing and grinding. This suggests that eleutherodontids are herbivorous, and probably specialized for granivory or feeding on soft plant tissues. The inferred dietary adaptation of eleutherodontid gliders represents a remarkable evolutionary convergence with herbivorous gliders in Theria. These Jurassic fossils represent volant, herbivorous stem mammaliaforms associated with pre-angiosperm plants that appear long before the later, iterative associations between angiosperm plants and volant herbivores in various therian clades.

]]>New evidence for mammaliaform ear evolution and feeding adaptation in a Jurassic ecosystemZhe-Xi LuoQing-Jin MengDavid M. GrossnickleDi LiuApril I. NeanderYu-Guang ZhangQiang Jidoi:10.1038/nature23483Nature 548, 7667 (2017)2017-08-09Nature2017-08-0910.1038/nature23483http://dx.doi.org/10.1038/nature234835487667Letter326329Rewiring the taste systemhttp://dx.doi.org/10.1038/nature23299
In mammals, taste buds typically contain 50–100 tightly packed taste-receptor cells (TRCs), representing all five basic qualities: sweet, sour, bitter, salty and umami. Notably, mature taste cells have life spans of only 5–20 days and, consequently, are constantly replenished by differentiation of taste stem cells. Given the importance of establishing and maintaining appropriate connectivity between TRCs and their partner ganglion neurons (that is, ensuring that a labelled line from sweet TRCs connects to sweet neurons, bitter TRCs to bitter neurons, sour to sour, and so on), we examined how new connections are specified to retain fidelity of signal transmission. Here we show that bitter and sweet TRCs provide instructive signals to bitter and sweet target neurons via different guidance molecules (SEMA3A and SEMA7A). We demonstrate that targeted expression of SEMA3A or SEMA7A in different classes of TRCs produces peripheral taste systems with miswired sweet or bitter cells. Indeed, we engineered mice with bitter neurons that now responded to sweet tastants, sweet neurons that responded to bitter or sweet neurons responding to sour stimuli. Together, these results uncover the basic logic of the wiring of the taste system at the periphery, and illustrate how a labelled-line sensory circuit preserves signalling integrity despite rapid and stochastic turnover of receptor cells.Rewiring the taste system

In mammals, taste buds typically contain 50–100 tightly packed taste-receptor cells (TRCs), representing all five basic qualities: sweet, sour, bitter, salty and umami. Notably, mature taste cells have life spans of only 5–20 days and, consequently, are constantly replenished by differentiation of taste stem cells. Given the importance of establishing and maintaining appropriate connectivity between TRCs and their partner ganglion neurons (that is, ensuring that a labelled line from sweet TRCs connects to sweet neurons, bitter TRCs to bitter neurons, sour to sour, and so on), we examined how new connections are specified to retain fidelity of signal transmission. Here we show that bitter and sweet TRCs provide instructive signals to bitter and sweet target neurons via different guidance molecules (SEMA3A and SEMA7A). We demonstrate that targeted expression of SEMA3A or SEMA7A in different classes of TRCs produces peripheral taste systems with miswired sweet or bitter cells. Indeed, we engineered mice with bitter neurons that now responded to sweet tastants, sweet neurons that responded to bitter or sweet neurons responding to sour stimuli. Together, these results uncover the basic logic of the wiring of the taste system at the periphery, and illustrate how a labelled-line sensory circuit preserves signalling integrity despite rapid and stochastic turnover of receptor cells.

]]>Rewiring the taste systemHojoon LeeLindsey J. MacphersonCamilo A. ParadaCharles S. ZukerNicholas J. P. Rybadoi:10.1038/nature23299Nature 548, 7667 (2017)2017-08-09Nature2017-08-0910.1038/nature23299http://dx.doi.org/10.1038/nature232995487667Letter330333Correction of aberrant growth preserves tissue homeostasishttp://dx.doi.org/10.1038/nature23304
Cells in healthy tissues acquire mutations with surprising frequency. Many of these mutations are associated with abnormal cellular behaviours such as differentiation defects and hyperproliferation, yet fail to produce macroscopically detectable phenotypes. It is currently unclear how the tissue remains phenotypically normal, despite the presence of these mutant cells. Here we use intravital imaging to track the fate of mouse skin epithelium burdened with varying numbers of activated Wnt/β-catenin stem cells. We show that all resulting growths that deform the skin tissue architecture regress, irrespective of their size. Wild-type cells are required for the active elimination of mutant cells from the tissue, while utilizing both endogenous and ectopic cellular behaviours to dismantle the aberrant structures. After regression, the remaining structures are either completely eliminated or converted into functional skin appendages in a niche-dependent manner. Furthermore, tissue aberrancies generated from oncogenic Hras, and even mutation-independent deformations to the tissue, can also be corrected, indicating that this tolerance phenomenon reflects a conserved principle in the skin. This study reveals an unanticipated plasticity of the adult skin epithelium when faced with mutational and non-mutational insult, and elucidates the dynamic cellular behaviours used for its return to a homeostatic state.Correction of aberrant growth preserves tissue homeostasis

Cells in healthy tissues acquire mutations with surprising frequency. Many of these mutations are associated with abnormal cellular behaviours such as differentiation defects and hyperproliferation, yet fail to produce macroscopically detectable phenotypes. It is currently unclear how the tissue remains phenotypically normal, despite the presence of these mutant cells. Here we use intravital imaging to track the fate of mouse skin epithelium burdened with varying numbers of activated Wnt/β-catenin stem cells. We show that all resulting growths that deform the skin tissue architecture regress, irrespective of their size. Wild-type cells are required for the active elimination of mutant cells from the tissue, while utilizing both endogenous and ectopic cellular behaviours to dismantle the aberrant structures. After regression, the remaining structures are either completely eliminated or converted into functional skin appendages in a niche-dependent manner. Furthermore, tissue aberrancies generated from oncogenic Hras, and even mutation-independent deformations to the tissue, can also be corrected, indicating that this tolerance phenomenon reflects a conserved principle in the skin. This study reveals an unanticipated plasticity of the adult skin epithelium when faced with mutational and non-mutational insult, and elucidates the dynamic cellular behaviours used for its return to a homeostatic state.

]]>Correction of aberrant growth preserves tissue homeostasisSamara BrownCristiana M. PinedaTianchi XinJonathan BoucherKathleen C. SuozziSangbum ParkCatherine Matte-MartoneDavid G. GonzalezJulie RytlewskiSlobodan BeronjaValentina Grecodoi:10.1038/nature23304Nature 548, 7667 (2017)2017-08-02Nature2017-08-0210.1038/nature23304http://dx.doi.org/10.1038/nature233045487667Letter334337m6A mRNA methylation controls T cell homeostasis by targeting the IL-7/STAT5/SOCS pathwayshttp://dx.doi.org/10.1038/nature23450
N6-methyladenosine (m6A) is the most common and abundant messenger RNA modification, modulated by ‘writers’, ‘erasers’ and ‘readers’ of this mark. In vitro data have shown that m6A influences all fundamental aspects of mRNA metabolism, mainly mRNA stability, to determine stem cell fates. However, its in vivo physiological function in mammals and adult mammalian cells is still unknown. Here we show that the deletion of m6A ‘writer’ protein METTL3 in mouse T cells disrupts T cell homeostasis and differentiation. In a lymphopaenic mouse adoptive transfer model, naive Mettl3-deficient T cells failed to undergo homeostatic expansion and remained in the naive state for up to 12 weeks, thereby preventing colitis. Consistent with these observations, the mRNAs of SOCS family genes encoding the STAT signalling inhibitory proteins SOCS1, SOCS3 and CISH were marked by m6A, exhibited slower mRNA decay and showed increased mRNAs and levels of protein expression in Mettl3-deficient naive T cells. This increased SOCS family activity consequently inhibited IL-7-mediated STAT5 activation and T cell homeostatic proliferation and differentiation. We also found that m6A has important roles for inducible degradation of Socs mRNAs in response to IL-7 signalling in order to reprogram naive T cells for proliferation and differentiation. Our study elucidates for the first time, to our knowledge, the in vivo biological role of m6A modification in T-cell-mediated pathogenesis and reveals a novel mechanism of T cell homeostasis and signal-dependent induction of mRNA degradation.m6A mRNA methylation controls T cell homeostasis by targeting the IL-7/STAT5/SOCS pathways

N6-methyladenosine (m6A) is the most common and abundant messenger RNA modification, modulated by ‘writers’, ‘erasers’ and ‘readers’ of this mark. In vitro data have shown that m6A influences all fundamental aspects of mRNA metabolism, mainly mRNA stability, to determine stem cell fates. However, its in vivo physiological function in mammals and adult mammalian cells is still unknown. Here we show that the deletion of m6A ‘writer’ protein METTL3 in mouse T cells disrupts T cell homeostasis and differentiation. In a lymphopaenic mouse adoptive transfer model, naive Mettl3-deficient T cells failed to undergo homeostatic expansion and remained in the naive state for up to 12 weeks, thereby preventing colitis. Consistent with these observations, the mRNAs of SOCS family genes encoding the STAT signalling inhibitory proteins SOCS1, SOCS3 and CISH were marked by m6A, exhibited slower mRNA decay and showed increased mRNAs and levels of protein expression in Mettl3-deficient naive T cells. This increased SOCS family activity consequently inhibited IL-7-mediated STAT5 activation and T cell homeostatic proliferation and differentiation. We also found that m6A has important roles for inducible degradation of Socs mRNAs in response to IL-7 signalling in order to reprogram naive T cells for proliferation and differentiation. Our study elucidates for the first time, to our knowledge, the in vivo biological role of m6A modification in T-cell-mediated pathogenesis and reveals a novel mechanism of T cell homeostasis and signal-dependent induction of mRNA degradation.

]]>m6A mRNA methylation controls T cell homeostasis by targeting the IL-7/STAT5/SOCS pathwaysHua-Bing LiJiyu TongShu ZhuPedro J. BatistaErin E. DuffyJun ZhaoWill BailisGuangchao CaoLina KroehlingYuanyuan ChenGeng WangJames P. BroughtonY. Grace ChenYuval KlugerMatthew D. SimonHoward Y. ChangZhinan YinRichard A. Flavelldoi:10.1038/nature23450Nature 548, 7667 (2017)2017-08-09Nature2017-08-0910.1038/nature23450http://dx.doi.org/10.1038/nature234505487667Letter338342Genome-scale activation screen identifies a lncRNA locus regulating a gene neighbourhoodhttp://dx.doi.org/10.1038/nature23451
Mammalian genomes contain thousands of loci that transcribe long noncoding RNAs (lncRNAs), some of which are known to carry out critical roles in diverse cellular processes through a variety of mechanisms. Although some lncRNA loci encode RNAs that act non-locally (in trans), there is emerging evidence that many lncRNA loci act locally (in cis) to regulate the expression of nearby genes—for example, through functions of the lncRNA promoter, transcription, or transcript itself. Despite their potentially important roles, it remains challenging to identify functional lncRNA loci and distinguish among these and other mechanisms. Here, to address these challenges, we developed a genome-scale CRISPR–Cas9 activation screen that targets more than 10,000 lncRNA transcriptional start sites to identify noncoding loci that influence a phenotype of interest. We found 11 lncRNA loci that, upon recruitment of an activator, mediate resistance to BRAF inhibitors in human melanoma cells. Most candidate loci appear to regulate nearby genes. Detailed analysis of one candidate, termed EMICERI, revealed that its transcriptional activation resulted in dosage-dependent activation of four neighbouring protein-coding genes, one of which confers the resistance phenotype. Our screening and characterization approach provides a CRISPR toolkit with which to systematically discover the functions of noncoding loci and elucidate their diverse roles in gene regulation and cellular function.Genome-scale activation screen identifies a lncRNA locus regulating a gene neighbourhood

Mammalian genomes contain thousands of loci that transcribe long noncoding RNAs (lncRNAs), some of which are known to carry out critical roles in diverse cellular processes through a variety of mechanisms. Although some lncRNA loci encode RNAs that act non-locally (in trans), there is emerging evidence that many lncRNA loci act locally (in cis) to regulate the expression of nearby genes—for example, through functions of the lncRNA promoter, transcription, or transcript itself. Despite their potentially important roles, it remains challenging to identify functional lncRNA loci and distinguish among these and other mechanisms. Here, to address these challenges, we developed a genome-scale CRISPR–Cas9 activation screen that targets more than 10,000 lncRNA transcriptional start sites to identify noncoding loci that influence a phenotype of interest. We found 11 lncRNA loci that, upon recruitment of an activator, mediate resistance to BRAF inhibitors in human melanoma cells. Most candidate loci appear to regulate nearby genes. Detailed analysis of one candidate, termed EMICERI, revealed that its transcriptional activation resulted in dosage-dependent activation of four neighbouring protein-coding genes, one of which confers the resistance phenotype. Our screening and characterization approach provides a CRISPR toolkit with which to systematically discover the functions of noncoding loci and elucidate their diverse roles in gene regulation and cellular function.

]]>Genome-scale activation screen identifies a lncRNA locus regulating a gene neighbourhoodJulia JoungJesse M. EngreitzSilvana KonermannOmar O. AbudayyehVanessa K. VerdineFrancois AguetJonathan S. GootenbergNeville E. SanjanaJason B. WrightCharles P. FulcoYuen-Yi TsengCharles H. YoonJesse S. BoehmEric S. LanderFeng Zhangdoi:10.1038/nature23451Nature 548, 7667 (2017)2017-08-09Nature2017-08-0910.1038/nature23451http://dx.doi.org/10.1038/nature234515487667Letter343346mRNA 3′ uridylation and poly(A) tail length sculpt the mammalian maternal transcriptomehttp://dx.doi.org/10.1038/nature23318
A fundamental principle in biology is that the program for early development is established during oogenesis in the form of the maternal transcriptome. How the maternal transcriptome acquires the appropriate content and dosage of transcripts is not fully understood. Here we show that 3′ terminal uridylation of mRNA mediated by TUT4 and TUT7 sculpts the mouse maternal transcriptome by eliminating transcripts during oocyte growth. Uridylation mediated by TUT4 and TUT7 is essential for both oocyte maturation and fertility. In comparison to somatic cells, the oocyte transcriptome has a shorter poly(A) tail and a higher relative proportion of terminal oligo-uridylation. Deletion of TUT4 and TUT7 leads to the accumulation of a cohort of transcripts with a high frequency of very short poly(A) tails, and a loss of 3′ oligo-uridylation. By contrast, deficiency of TUT4 and TUT7 does not alter gene expression in a variety of somatic cells. In summary, we show that poly(A) tail length and 3′ terminal uridylation have essential and specific functions in shaping a functional maternal transcriptome.mRNA 3′ uridylation and poly(A) tail length sculpt the mammalian maternal transcriptome

A fundamental principle in biology is that the program for early development is established during oogenesis in the form of the maternal transcriptome. How the maternal transcriptome acquires the appropriate content and dosage of transcripts is not fully understood. Here we show that 3′ terminal uridylation of mRNA mediated by TUT4 and TUT7 sculpts the mouse maternal transcriptome by eliminating transcripts during oocyte growth. Uridylation mediated by TUT4 and TUT7 is essential for both oocyte maturation and fertility. In comparison to somatic cells, the oocyte transcriptome has a shorter poly(A) tail and a higher relative proportion of terminal oligo-uridylation. Deletion of TUT4 and TUT7 leads to the accumulation of a cohort of transcripts with a high frequency of very short poly(A) tails, and a loss of 3′ oligo-uridylation. By contrast, deficiency of TUT4 and TUT7 does not alter gene expression in a variety of somatic cells. In summary, we show that poly(A) tail length and 3′ terminal uridylation have essential and specific functions in shaping a functional maternal transcriptome.

]]>mRNA 3′ uridylation and poly(A) tail length sculpt the mammalian maternal transcriptomeMarcos MorganChristian MuchMonica DiGiacomoChiara AzziIvayla IvanovaDimitrios M. VitsiosJelena PistolicPaul CollierPedro N. MoreiraVladimir BenesAnton J. EnrightDónal O’Carrolldoi:10.1038/nature23318Nature 548, 7667 (2017)2017-08-09Nature2017-08-0910.1038/nature23318http://dx.doi.org/10.1038/nature233185487667Letter347351Cryo-EM structure of the protein-conducting ERAD channel Hrd1 in complex with Hrd3http://dx.doi.org/10.1038/nature23314
Misfolded endoplasmic reticulum proteins are retro-translocated through the membrane into the cytosol, where they are poly-ubiquitinated, extracted from the membrane, and degraded by the proteasome—a pathway termed endoplasmic reticulum-associated protein degradation (ERAD). Proteins with misfolded domains in the endoplasmic reticulum lumen or membrane are discarded through the ERAD-L and ERAD-M pathways, respectively. In Saccharomyces cerevisiae, both pathways require the ubiquitin ligase Hrd1, a multi-spanning membrane protein with a cytosolic RING finger domain. Hrd1 is the crucial membrane component for retro-translocation, but it is unclear whether it forms a protein-conducting channel. Here we present a cryo-electron microscopy structure of S. cerevisiae Hrd1 in complex with its endoplasmic reticulum luminal binding partner, Hrd3. Hrd1 forms a dimer within the membrane with one or two Hrd3 molecules associated at its luminal side. Each Hrd1 molecule has eight transmembrane segments, five of which form an aqueous cavity extending from the cytosol almost to the endoplasmic reticulum lumen, while a segment of the neighbouring Hrd1 molecule forms a lateral seal. The aqueous cavity and lateral gate are reminiscent of features of protein-conducting conduits that facilitate polypeptide movement in the opposite direction—from the cytosol into or across membranes. Our results suggest that Hrd1 forms a retro-translocation channel for the movement of misfolded polypeptides through the endoplasmic reticulum membrane.Cryo-EM structure of the protein-conducting ERAD channel Hrd1 in complex with Hrd3

Misfolded endoplasmic reticulum proteins are retro-translocated through the membrane into the cytosol, where they are poly-ubiquitinated, extracted from the membrane, and degraded by the proteasome—a pathway termed endoplasmic reticulum-associated protein degradation (ERAD). Proteins with misfolded domains in the endoplasmic reticulum lumen or membrane are discarded through the ERAD-L and ERAD-M pathways, respectively. In Saccharomyces cerevisiae, both pathways require the ubiquitin ligase Hrd1, a multi-spanning membrane protein with a cytosolic RING finger domain. Hrd1 is the crucial membrane component for retro-translocation, but it is unclear whether it forms a protein-conducting channel. Here we present a cryo-electron microscopy structure of S. cerevisiae Hrd1 in complex with its endoplasmic reticulum luminal binding partner, Hrd3. Hrd1 forms a dimer within the membrane with one or two Hrd3 molecules associated at its luminal side. Each Hrd1 molecule has eight transmembrane segments, five of which form an aqueous cavity extending from the cytosol almost to the endoplasmic reticulum lumen, while a segment of the neighbouring Hrd1 molecule forms a lateral seal. The aqueous cavity and lateral gate are reminiscent of features of protein-conducting conduits that facilitate polypeptide movement in the opposite direction—from the cytosol into or across membranes. Our results suggest that Hrd1 forms a retro-translocation channel for the movement of misfolded polypeptides through the endoplasmic reticulum membrane.

]]>Cryo-EM structure of the protein-conducting ERAD channel Hrd1 in complex with Hrd3Stefan SchoebelWei MiAlexander SteinSergey OvchinnikovRyan PavloviczFrank DiMaioDavid BakerMelissa G. ChambersHuayou SuDongsheng LiTom A. RapoportMaofu Liaodoi:10.1038/nature23314Nature 548, 7667 (2017)2017-07-06Nature2017-07-0610.1038/nature23314http://dx.doi.org/10.1038/nature233145487667Letter352355Structural insights into ligand recognition by the lysophosphatidic acid receptor LPA6http://dx.doi.org/10.1038/nature23448
Lysophosphatidic acid (LPA) is a bioactive lipid composed of a phosphate group, a glycerol backbone, and a single acyl chain that varies in length and saturation. LPA activates six class A G-protein-coupled receptors to provoke various cellular reactions. Because LPA signalling has been implicated in cancer and fibrosis, the LPA receptors are regarded as promising drug targets. The six LPA receptors are subdivided into the endothelial differentiation gene (EDG) family (LPA1–LPA3) and the phylogenetically distant non-EDG family (LPA4–LPA6). The structure of LPA1 has enhanced our understanding of the EDG family of LPA receptors. By contrast, the functional and pharmacological characteristics of the non-EDG family of LPA receptors have remained unknown, owing to the lack of structural information. Although the non-EDG LPA receptors share sequence similarity with the P2Y family of nucleotide receptors, the LPA recognition mechanism cannot be deduced from the P2Y1 and P2Y12 structures because of the large differences in the chemical structures of their ligands. Here we determine the 3.2 Å crystal structure of LPA6, the gene deletion of which is responsible for congenital hair loss, to clarify the ligand recognition mechanism of the non-EDG family of LPA receptors. Notably, the ligand-binding pocket of LPA6 is laterally open towards the membrane, and the acyl chain of the lipid used for the crystallization is bound within this pocket, indicating the binding mode of the LPA acyl chain. Docking and mutagenesis analyses also indicated that the conserved positively charged residues within the central cavity recognize the phosphate head group of LPA by inducing an inward shift of transmembrane helices 6 and 7, suggesting that the receptor activation is triggered by this conformational rearrangement.Structural insights into ligand recognition by the lysophosphatidic acid receptor LPA6

Lysophosphatidic acid (LPA) is a bioactive lipid composed of a phosphate group, a glycerol backbone, and a single acyl chain that varies in length and saturation. LPA activates six class A G-protein-coupled receptors to provoke various cellular reactions. Because LPA signalling has been implicated in cancer and fibrosis, the LPA receptors are regarded as promising drug targets. The six LPA receptors are subdivided into the endothelial differentiation gene (EDG) family (LPA1–LPA3) and the phylogenetically distant non-EDG family (LPA4–LPA6). The structure of LPA1 has enhanced our understanding of the EDG family of LPA receptors. By contrast, the functional and pharmacological characteristics of the non-EDG family of LPA receptors have remained unknown, owing to the lack of structural information. Although the non-EDG LPA receptors share sequence similarity with the P2Y family of nucleotide receptors, the LPA recognition mechanism cannot be deduced from the P2Y1 and P2Y12 structures because of the large differences in the chemical structures of their ligands. Here we determine the 3.2 Å crystal structure of LPA6, the gene deletion of which is responsible for congenital hair loss, to clarify the ligand recognition mechanism of the non-EDG family of LPA receptors. Notably, the ligand-binding pocket of LPA6 is laterally open towards the membrane, and the acyl chain of the lipid used for the crystallization is bound within this pocket, indicating the binding mode of the LPA acyl chain. Docking and mutagenesis analyses also indicated that the conserved positively charged residues within the central cavity recognize the phosphate head group of LPA by inducing an inward shift of transmembrane helices 6 and 7, suggesting that the receptor activation is triggered by this conformational rearrangement.